It is proposed to develop methodology which will permit synthesis of natural hemes regioselectively labeled in predetermined positions with deuterium, carbon-13, tritium, nitrogen-15, and fluorine, and this methodology will subsequently be used by others for synthesis of NMR and resonance Raman probes to gain an understanding of heme apoprotein interactions and structure/function relationships in a variety of biologically important heme proteins such as hemoglobins, myoglobins, cytochromes, and peroxidases. It is also proposed to synthesize a variety of unlabeled heme analogues, heme dimers, sulfhemes, and hydrohemes. The structure of heme-dl will be re-examined and biosynthetic studies will be performed to establish the pathway to this unusual isobacteriochlorin system. Investigations into novel rearrangement processes in porphyrin systems, and a synthesis of an optically active N-methyporphyrin known to be a ferrochelatase inhibitor will also be carried out. The proposed work will provide a basis for understanding heme protein function, and of structural and electronic factors which cause several debilitating diseases such as anemias. Two fundamental approaches for synthesis of novel compounds will be developed;. carbon-13, nitrogen-15, fluorine labeled, and unlabeled porphyrins will be obtained by total synthesis from acyclic precursors. Some methods for such approaches have already been worked out, but improvements and discovery of new methodology is planned and anticipated. Some deuterium labeled, carbon-13 labeled porphyrins, protoporphyrin IX analogues, and sulfhemes, N-methylporphyrins and other chlorin hemes will be approached by manipulation of substituents on existing commercially available porphyrins or from chlorophyll alpha which will be extracted from a commercially available alga.